ArticleHuman mutation2018
Quantifying the potential of functional evidence to reclassify variants of uncertain significance in the categorical and Bayesian interpretation frameworks.
Article in Human mutation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Pooled it
- Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels.Genome medicine · 2019Pooled it
- The average individual genome: a survey of nearly 1 million whole-genome sequences.Genome medicine · 2026Article
- sortscore: Sort-seq MAVE scoring and visualization using Python.Bioinformatics (Oxford, England) · 2026Article
- Cascade screening and genetic variant pathogenicity assessment for familial hypercholesterolemia in a township‑based elderly population.Lipids in health and disease · 2026Article
- Genetic analysis and reproductive interventions in families affected by congenital cataracts: a study of 107 cases.Journal of applied genetics · 2026Article
- An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Assessing Allele Frequency Information: A Study of Variant Curation Expert Panel Guidelines.Human mutation · 2026Article
- RNA-guided clarity: The potential for resolving variant uncertainty in clinical exome sequencing.Genetics in medicine open · 2026Article
- Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization.American journal of ophthalmology · 2025Observational
- Consultation informs strategies for improving the use of functional evidence in variant classification.American journal of human genetics · 2025Article
- Cracking rare disorders: a new minimally invasive RNA-seq protocol.NPJ genomic medicine · 2025Article
- Maternal mixed UPD3 and a homozygous PLXNA1 c.2497G>C variant in a fetus with severe anomalies.Frontiers in medicine · 2025Article
- The Challenge of VUS in Inherited Retinal Degeneration: Insight from Functional Studies.Advances in experimental medicine and biology · 2025Review
- A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis.European journal of neurology · 2024Article
- Assigning credit where it is due: an information content score to capture the clinical value of multiplexed assays of variant effect.BMC bioinformatics · 2024Article
- The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.Journal of human genetics · 2024Article
- Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss.Genome medicine · 2023Article
- Relevance of next generation sequencing (NGS) data re-analysis in the diagnosis of monogenic diseases leading to organ failure.BMC medical genomics · 2023Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Additional variant interpretation tools are required to effectively harness genomic sequencing for clinical applications. The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) published guidelines for clinical sequence variant interpretation, incorporating different types of data that lend varying levels of support towards a benign or pathogenic interpretation. Variants of uncertain significance (VUS) are those with either contradictory or insufficient evidence, and their uncertainty complicates patient counseling and management. Functional assays may provide a solution to evidence gaps relegating variants to the VUS category, but the impact of functional evidence in this framework has not been assessed. We employ an algorithmic analysis of the ACMG/AMP combining rules to assess how the availability of strong functional evidence could theoretically improve the ability to make a benign or pathogenic assertion. We follow this with analysis of actual evidence combinations met by variants through expert curations as part of the Clinical Genome Resource (ClinGen). We also examine the impact of functional evidence in a Bayesian adaptation of the ACMG/AMP framework. This lays the groundwork for an evidence-based prioritization of assay development and variant assessment by identifying genes and variants that may benefit the most from functional data.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.